Depression increases the risk for cardiac morbidity and mortality 2-4 fold in patients with coronary heart disease (CHD). Recent clinical trials have tested standard treatments for comorbid depression in patients with CHD, and some have evaluated their effects on cardiac morbidity and mortality. Most of these trials have shown that standard treatments have only modest effects on depression and have produced relatively small differences between the intervention and control condition. Consequently, they have been unable to determine whether effective treatment of depression can improve cardiac outcomes. Low dietary intake and low plasma phospholipid or erythrocyte levels of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with depression and other cardiac risk markers, including ones that may mediate the relationship between depression and cardiac mortality. There is growing evidence from small psychiatric trials that the efficacy of standard antidepressants can be improved by coadministration of an omega-3 FA formulation containing at least 1 gram of EPA with a ratio of between 2 to 4 parts EPA to 1 part DHA (2-4EPA:1DHA). The purpose of the proposed research is to determine whether antidepressant augmentation with this omega-3 FA formulation is superior to antidepressant therapy alone for major depression in patients with CHD, and to investigate its effects on other cardiac risk markers in these patients. The proposed study is a randomized, placebo-controlled, double-blind clinical trial. Patients who meet the DSM-IV-TR criteria for a major depressive episode 2-4 months after an acute coronary syndrome (ACS) will be given 25 mg/day of sertraline plus two placebo capsules for 14 days. The first 170 participants who continue to meet the DSM-IV-TR criteria for major depression, score e15 on the Hamilton Rating Scale for Depression (HAM-D), report no serious side effects, and take both drugs >90% of days, will undergo a baseline evaluation and then be randomly assigned to receive either 50 mg/day of sertraline plus omega-3 FA or 50 mg/day of sertraline plus placebo for 10 weeks. At baseline and after 10 weeks, participants will complete assessments of depression, 24 hour ambulatory ECG monitoring to measure 24 hour heart rate and heart rate variability, and blood draws to measure procoagulant and proinflammatory markers and blood levels of EPA, DHA, other omega-3 FAs, and the omega-6 FAs. If sertraline plus this omega-3 formulation significantly reduces depression compared to sertraline plus placebo, and if it improves or at least does not worsen other cardiovascular risk markers, this study will provide a strong basis for proposing a multicenter clinical trial of sertraline augmented with omega-3 to determine whether treatment of depression can improve survival in patients with post-ACS depression.